CDK4/6 inhibitor-mediated cell overgrowth triggers osmotic and replication stress to promote senescence

Area of Science:

• Cell Biology
• Molecular Biology
• Cancer Research

Background:

• Abnormal cell size increases are linked to senescence and cell cycle exit.
• The mechanisms connecting cell overgrowth to cell cycle withdrawal are not fully understood.
• CDK4/6 inhibitors are approved for treating advanced HR+/HER2- breast cancer by arresting cells in G0/G1.

Purpose of the Study:

• To investigate the mechanisms by which cell overgrowth primes cells for cell cycle withdrawal.
• To elucidate the role of p38/p53/p21 signaling in CDK4/6 inhibitor-induced cell cycle arrest.
• To understand the biphasic nature of p21 induction and its impact on cell fate.

Main Methods:

• Utilized CDK4/6 inhibitors to induce cell cycle arrest in G0/G1.
• Monitored cell size changes and p21 induction.
• Investigated p38 and p53 activation.
• Performed inhibitor washout experiments to assess cell cycle reentry and subsequent stress responses.

Main Results:

• CDK4/6-inhibited cells exhibit overgrowth during G0/G1.
• Cell cycle withdrawal is dependent on p38/p53/p21 signaling.
• p21 is induced in two waves: the first by osmotic stress and size, the second by replication stress upon washout.
• Overgrown cells experience replication stress, leading to delayed cell cycle withdrawal.

Conclusions:

• Cellular hypertrophy during CDK4/6 inhibition drives cell cycle withdrawal through a p38/p53/p21-dependent pathway.
• Biphasic p21 induction integrates signals from overgrowth-induced stresses to dictate cell fate.
• This model provides insight into how hypertrophy promotes senescence and explains the sustained efficacy of CDK4/6 inhibitors in patients.